Project Summary Despite the remarkable progress in drug development over the past 20 years, antiretroviral treatment success is not universal. The most frequent cause of treatment failure in both therapeutic and prophylactic settings continues to be challenges associated with drug adherence. Although many patients can manage daily adherence for substantial periods of time, treatment fatigue as well as special difficulties exist for vulnerable patient populations including those challenged by substance abuse, mental illness, prolonged periods away from home and stigma within their communities. All too often treatment failure ensues. This has led to an increasing interest in the development of antiretroviral chemotherapeutic agents that can be given at prolonged dosing intervals. Several novel compounds and compounding approaches have emerged that suggest this goal is highly attainable. In this application we wish to develop an effective approach to deliver the globally used nucleotide, tenofovir, to the list of agents that can be administered at monthly intervals. We have demonstrated that ester linkage of an alkoxyalkyl side chain to the parent molecule greatly enhances cellular uptake and that we can modify the rate of intracellular release by the addition of a second promoiety at the remaining phosphonate oxygen. The combined effect of these modifications results in rapid cellular uptake and sustained ?timed-release? delivery of tenofovir diphosphate to the intracellular compartment. One lead compound, the octadecyloxyethyl benzyl diester of tenofovir (ODE-Bn-TFV), has single nanomolar anti-HIV activity and a selectivity index of >3000. Tenofovir diphosphate was slowly liberated in the intracellular compartment where it maintained a half-life of more than a week. We propose to utilize this approach to develop additional compounds of even greater potency and intracellular half-life. We will compound our novel time-release molecules in nanoparticles that will slowly release these molecules into the systemic circulation from the site of intramuscular injection. We believe that by using nanotechnology to first modulate release of prodrug into the systemic circulation and then using a synthetic chemical approach to enhance cellular uptake and to slow intracellular decay that we can deliver potent antiviral activity to sites of viral replication for a month following intramuscular injection.